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PMID: 18505733 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The RNA-stabilizing protein HuR regulates the expression of zeta chain of the human T cell receptor-associated CD3 complex.

The Journal of biological chemistry ·Vol. 283 ·No. 29 ·2008-07-18 ·Pages 20037-44

Moulton VR, Kyttaris VC, Juang YT, Chowdhury B, Tsokos GC

Abstract

T cell dysfunction is crucial to the pathogenesis of systemic lupus erythematosus (SLE); however, the molecular mechanisms involved in the deficient expression of the T cell receptor-associated CD3zeta chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3zeta that lacks a 562-bp region in its 3'-untranslated region (UTR). We showed previously that two adenosine/uridine-rich elements (ARE) in this splice-deleted region of CD3zeta transcript are critical for the mRNA stability and protein expression of CD3zeta. In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3zeta 3'-UTR. Knockdown of HuR resulted in decreased expression of the CD3zeta chain, whereas overexpression led to the increase of CD3zeta chain levels. Additionally, overexpression of HuR in human T cells resulted in increased mRNA stability of CD3zeta. Our results identify the 3'-UTR of CD3zeta as a novel target for the mRNA-stabilizing protein HuR. Thus, the absence of two critical AREs in the alternatively spliced CD3zeta 3'-UTR found in SLE T cells may result in decreased HuR binding, representing a possible molecular mechanism contributing to the reduced stability and expression of CD3zeta in SLE.

MeSH Terms
3' Untranslated Regions/genetics Antigens, Surface/genetics,metabolism CD3 Complex/genetics,metabolism ELAV Proteins ELAV-Like Protein 1 Gene Expression Regulation Humans Jurkat Cells Molecular Sequence Data Protein Binding RNA Stability RNA-Binding Proteins/genetics,metabolism Response Elements
Chemicals
3' Untranslated Regions Antigens, Surface CD3 Complex CD3 antigen, zeta chain ELAV Proteins ELAV-Like Protein 1 ELAVL1 protein, human RNA-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Moulton Vaishali R
Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Kyttaris Vasileios C
Juang Yuang-Taung
Chowdhury Bhabadeb
Tsokos George C
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M710434200
Published
2008-07-18
Epub
2008-00-27
Pages
20037-44
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2459291
Subset
IM
Grants
NIAMS NIH HHS · K23 AR055672 · United States
NIAMS NIH HHS · K23 AR055672-01A1 · United States
NIAID NIH HHS · R01 AI042269 · United States
NIAID NIH HHS · R01 AI 42269 · United States
External Links
PubMed source DOI: 10.1074/jbc.M710434200 PMC Full Text View journal details
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